Mercury and lead are pervasive in the environment and pose a severe risk to human health worldwide. The purpose of the proposed research is to develop new and innovative detoxification strategies for these metals. Organomercury compounds, in particular, are highly toxic as illustrated by the death of almost two thousand people around Minamata Bay (Japan) in the late 1950s when the residents consumed fish that were contaminated with methyl mercury compounds. Furthermore, the use of organomercurials as pesticides resulted in the death of ca 500 people in Iraq in the early 1970s when wheat seeds treated with these pesticides were used for making bread rather than for growing wheat. While the outbreak of methyl mercury poisoning in Japan was a result of toxic release from a nearby chemical plant, methyl mercury compounds are also introduced into the environment by biomethylation of naturally occurring Hg(II) in an aquatic environment and accumulate in predatory fish. Likewise, the occurrence of lead in the environment is a consequence of its current and previous widespread use in, for example, batteries, gasoline, plumbing and paints, such that lead poisoning is the most common environmentally induced disease among children in the United Stated today. It is, therefore, evident that the discovery of improved detoxification strategies for metals such as mercury and lead would be of considerable benefit for human health. A central component of the proposed research will be to elucidate the biological chemistry of these metals that will facilitate detoxification. This objective will be achieved by using a synthetic analogue approach in which small molecules are used to mimic the biological system. Since the toxic effects of mercury and lead are largely a consequence of the ability of these metals to bind effectively to the cysteine residues of proteins, specific emphasis will be given to the application of ligands that feature sulfur donors. The protolytic cleavage of the Hg-C bond is an important component of mercury detoxification in bacteria and so considerable effort will be directed towards understanding the factors that influence this process, so that improved detoxification strategies can be developed for human applications. In this regard, the primary treatment of heavy metal poisoning is chelation therapy, but the effectiveness of this technique is far from ideal. Therefore, new strategies for chelation therapy will be developed by directing effort towards discovering molecules that chelate toxic metals more effectively. For example, multidentate ligands that feature arenethiol groups will be investigated since these groups may serve the dual purpose of both cleaving a Hg-C bond and coordinating the mercury. Furthermore, effort will be directed towards discovering compounds that promote Hg-C bond cleavage in vivo, and which may be used in conjunction with traditional chelating agents. Both of these approaches are important because they represent significant advances over the methods currently employed. PUBLIC HEALTH RELEVANCE: Mercury and lead are the two most toxic metals that are commonly encountered in the environment and are a severe risk to human health worldwide; as such, the discovery of improved detoxification strategies for these metals is of considerable importance to public health issues. A specific objective of the proposed research is to elucidate the chemistry of toxic metals in biological systems in order to enable the discovery of desperately needed new detoxification strategies. The proposed research is, therefore, relevant to the NIH mission of developing fundamental information that serves to reduce the burden of human illness.